1. Field of the Invention
The present invention is a method of preparing the inhalation anesthetic, fluoromethyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether (also known as sevoflurane), by an equilibrium process wherein the equilibrium is favorably shifted by removal of the product by distillation under active equilibrium conditions or by extraction of the product from the equilibrium mixture. This method is based on commercially available starting materials, produces higher yields of the desired product, and is more economical than prior art methods.
2. Description of Related Art
A number of methods have been disclosed for preparing sevoflurane (SVF). U.S. Pat. No. 3,683,092 and 3,689,571 describe the replacement of chlorine in chloromethyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether with fluorine using potassium fluoride in a solvent, sulfolane, at 120xc2x0 C., and U.S. Pat. No. 4,874,901 discloses the replacement without added solvent at high temperature (185xc2x0 C.) and pressure (280 psi). Other fluorinating reagents were also used to replace the chlorine. U.S. Pat. No. 5,886,239 uses diisopropylethylamine hydrofluoride, and the European Patent Appl. EP 0 901 999 A1 uses a mixture of an amine and hydrogen fluoride (HF). The starting material, chloromethyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether, is not commercially available. According to U.S. Pat. No. 3,683,092 it is prepared by the chlorination of methyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether, which can be synthesized from 1,1,1,3,3,3-hexafluoro-2-propanol, as described in U.S. Pat. No. 3,911,024.
Direct fluorination of methyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether to SVF is claimed using extremely reactive and expensive reagents such as bromine trifluoride in U.S. Pat. No. 3,683,092, and 20% molecular fluorine in argon in U.S. Pat. No. 3,897,502.
Another route to SVF, disclosed in U.S. Pat. No. 4,874,902, uses 1,1,1,3,3,3-hexachloro-2-propanol as starting material which is converted to methyl 2,2,2-trichloro-1-(trichloromethyl)ethyl ether, and then fluorinated with bromine trifluoride to give SVF. Alternatively, methyl 2,2,2-trichloro-1-(trichloromethyl)ethyl ether is chlorinated, and the corresponding chloromethyl ether is multipli-fluorinated using bromine trifluoride.
U.S. Pat. No. 5,705,710 describes preparation of SVF by fluorination of methoxymalononitrile using bromine trifluoride.
The above-mentioned methods of preparation of SVF are multi-step, or based on commercially unavailable starting materials, or use dangerous reagents.
Direct fluoromethylation to SVF of commercially available 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) is described in several patents. In U.S. Pat. No. 4,250,334, HFIP, HF and formaldehyde (CH2O) are heated in the presence of concentrated sulfric acid to continuously produce SVF collected in a cold trap.
According to U.S. Pat. No. 4,469,898, the yields of SVF are improved by adding excess sulfuric acid or other additives to sequester the water produced in the fluoromethylation of HFIP.
(CF3)2CHxe2x80x94OH+HF+CH2O⇄(CF3)2CHxe2x80x94Oxe2x80x94CH2F+H2O
However, a substantial amount of concentrated sulfuric acid or other Bronsted and/or Lewis acid (ca. 3 times greater then HFIP by weight) should be used to achieve 76-78% yield. As a result, large amounts of wastes (inorganic and organic) are made by the process.
PCT Int. Appl. WO 97/25303 discloses preparation of SVF by the reaction of HFIP with bis(fluoromethyl)ether in the presence of sulfuric acid, in which the desired product is produced with 55-60% yield along with an acetal by-product.
If no sulfuric acid or dehydrating, protonating and fluoride ion generating agent is used, the yields of SVF were very low, as was shown in the abandoned U.S. patent application Ser. No. 771,365, filed Oct. 28, 1968, and also in U.S. Pat. No. 3,689,571.
The present invention provides a method for the preparation of SVF by reacting HFIP with CH2O and HF under conditions wherein the desired product SVF is removed from the ongoing equilibrium either A) by distillation or B) by extraction.
A low-boiling azeotrope of SVF and HF was discovered so where SVF is removed by distillation, it is removed as an azeotrope with HF. During this process, water is also removed by distillation of the constant boiling mixture of water and HF (b.p. 115xc2x0 C.). SVF, removed as the HF azeotrope, is separated from HF by several methods: (i), washing the mixture with water, (ii), extracting with solvents dissolving SVF but not HF, (iii), cooling the azeotrope to separate layers, and (iv), distilling the SVF/HF azeotrope at the different pressures to obtain a mixture enriched in SVF.
In the extraction process, SVF is removed from the equilibrium by a solvent capable of selectively dissolving SVF and other reaction products but not starting materials and water.
1. Removal of SVF by Distillation during Reaction
One preferred embodiment of the invention involves running the fluoromethylation reaction during distillation. This is accomplished by having a reactor equipped with two columns. One is used to separate, as an overhead product, the HF/SVF mixture from the vapor over the equilibrium mixture. We discovered that SVF and HF form the low-boiling azeotrope described in Table 4. The other column is fed from the liquid in the reactor and removes the HF/water constant boiling mixture as a bottoms product. The overhead distillate from this second column is recycled to the reactor.
In practice, the HF/SVF azeotrope distillate may contain excess HF because the azeotrope boils only slightly lower than HF. [The use of the words SVF/HF azeotrope throughout the text is meant to include the actual azeotrope and the azeotrope when it includes excess HF.] The overhead from the first column, which is called xe2x80x9cHF/SVF azeotropexe2x80x9d will proceed to one of several separation methods to obtain pure SVF and return HF to the reaction/distillation process.
A. Separation of the HF/SVF Azeotrope to Obtain Pure SVF
The HF/SVF azeotrope can be separated very simply by washing the HF out with water. The SVF has a purity of about 99%.
As an alternative to water, SVF can be separated from HF by extraction with a large variety of suitable solvents, which are insoluble in hydrogen fluoride (see Section 2, infra). Following the extraction of SVF, HF can be recycled to the reaction and the SVF can be separated from the solvent and purified to the desired purity.
Another approach to separating SVF from HF is to cool the mixture. Upon cooling, separation begins at a lower temperature depending upon the composition of the HF/SVF mixture. The SVF/HF ratios are different in each layer. The separated layer with the enriched SVF can be distilled to obtain the SVF/HF azeotrope as the lower boiling product and excess SVF as the higher boiling product. The layer enriched in HF can be returned to the reaction/distillation process.
Still another means of separating SVF/HF is by varying the composition of the SVF/HF azeotrope through the use of different pressures (Table 4). An azeotropic composition that has a higher SVF content can be distilled at a different pressure to give an azeotrope containing less SVF as the lower boiling product and the excess SVF as the pure higher boiling product.
B. Recovery of Byproducts
Four major byproducts: bis{[2,2,2-trifluoro-1-(trifluoromethyl)ethoxy]methyl}ether (compound A), formaldehyde di[2,2,2-trifluoro-1-(trifluoromethyl)ethyl]acetal (compound B), formaldehyde fluoromethyl[2,2,2-trifluoro- 1 -(trifluoromethyl)ethyl]acetal (compound C), and bis(fluoromethyl) ether (compound D) were found. In a batch run it was found that their concentrations decreased to almost undetected levels by the end of distillation. All four compounds will react as well during a continuous distillation generating additional SVF by way of the following equilibria. 
These byproducts are reported in the literature (U.S. Pat. Nos. 3,689,571 and 4,469,898, Int. Appl., WO 97/30961, and Int. Appl. WO 97/25303) where they were used as a source of SVF.
In view of the chemistry described above, it is obvious that polyethers of general formula R1O(CH2O)nR2, in which n is a small number and R1 and R2 are hydrogens, alkyl groups, or haloalkyl groups, but both R1 and R 2 are not hydrogens in one formula, will revert to their starting materials under reaction/distillation conditions. Where the haloalkyl group is 1,1,1,3,3,3-hexafluoro-2-propyl SVF will be formed.
C. General Conditions
It will be obvious to those skilled in the art that this distillation under reaction conditions can be done either in a batch manner or continuously. Under continuous conditions the reactants would be added to the distillation system with the amounts of new components reduced by the amounts of reactants being continuously recycled. The reaction/distillation should be run continuously with columns capable of separating the SVF azeotrope from the other reactants and the constant boiling mixture of water and HF and of sufficient size, including the reboiler, to maintain the throughput desired. In this process, the equipment associated with the separation of HF and SVF would also provide the pure SVF and streams for recycle continuously. Conditions should be adjusted so they are close to optimum for both reaction and distillation.
The reaction should be conducted with the stoichiometric excess of HF in order to drive the equilibrium forward, and to provide for the HF/SVF and HF/H2O azeotropes. The process runs well with 15-18, or preferably with 25-30 mole equivalents of HF to HFIP.
The term xe2x80x9cformaldehydexe2x80x9d (CH2O) as used throughout this application, unless otherwise noted, is intended to include formaldehyde polymers, such as trioxane, which is preferred, and paraformaldehyde.
The reaction temperature is not critical, but the yields are substantially improved above 50xc2x0 C. Preferably, the reactive distillation can be conducted under autogenous pressure of 30-40 psig ensuring pot temperatures 45-75 xc2x0 C.
2. Removal of SVF by Extraction during Reaction
In a second preferred embodiment, the invention involves extracting the SVF product from the reaction mixture during the ongoing reaction.
The requirements for suitable solvents for this extraction are as follows:
1. The solvent should selectively extract SVF from the fluoromethylation mixture and not extract HFIP.
2. It should be hydrophobic.
3. It should not extract substantial amounts of HF.
4. It should not extract substantial amounts of CH2O or its polymeric forms.
5. The solvent should be easily separable from SVF.
A. Suitability of Various Solvents to Extract SVF
Several non-polar solvents have been evaluated for their ability to extract SVF and HFIP from HF. The partitions of SVF and of HFIP in solvent/HF system were measured by mixing a small amount of either SVF or HFIP with a two-layer mixture of equal volumes of a particular solvent and HF at 25xc2x0 C. After enough mixing to reach equilibrium, the fraction of original compound found in the solvent was determined by Gas Chromatography (GC) and quantified using standards. The data are given in Table 1.
As Table 1 demonstrates, a large variety of solvents are capable of extracting SVF from HF. Of these solvents it appears that the HC-0.8 oil is superior. On the other hand, none of the solvents studied extracted any significant amounts of HFIP from HF. From these data would appear that CFC solvents would also be good candidates for extraction. Hence, chlorofluorocarbons, chlorohydrocarbons, perfluorohydrocarbons, perfluoroethers, hydrocarbons and other solvents satisfying the requirements mentioned above are expected to be suitable for shifting the equilibrium.
B. General Conditions
While the order of addition of reactants is not critical, the reaction was conducted by adding HFIP to the mixture of anhydrous HF, formaldehyde and HC-0.8 under agitation. SVP and other products (see below) were extracted by the solvent. The layers were separated and more HC-0.8 oil was added and the reaction was continued until no further progress was seen.
The reaction temperature is not critical, but the reaction time and yields were substantially improved above 50xc2x0 C. Preferably, the reaction temperature should be maintained 60-70xc2x0 C. To achieve high conversion, both HF and CH2O should be present in excess of HFIP. Preferably, 50-100% molar excess of CH2O, and up to 1000 molar excess HF were used.
The amount of solvent to be used for extraction is not important because it could be easily recycled after distilling SVF. In batch reactions the frequency of extractions is an important factor to efficiently shift the equilibrium and shorten reaction time. Ideally, the process should be conducted under continuous extraction conditions.
As indicated previously according to U. S. Pat. No. 4,469,898, the yields of SVF are improved by adding excess sulfuric acid or other additives to sequester the water produced in the fluoromethylation of HFIP. HF is known to function as a water sequestering agent. Accordingly, the teaching of U.S. Pat. No. 4,469,898 is to employ additional water sequestering agents. It has been found that in the context of the present invention such use of additional water sequestering agents is unnecessary, and the extraction process can advantageously be carried out in the absence of a water sequestering agent other than the HF starting material.
C. Recovery of Byproducts
In addition to four major byproducts (A-D) extracted with SVF from the reaction mixture by HC-0.8, there was also small amount of formaldehyde methyl[2,2,2-trifluoro-1-(trifluoromethyl)ethyl]acetal (compound E) found after distillation.
(CF3)2CHxe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94CH3xe2x80x83xe2x80x83E
In a typical example, the composition of products in HC-0.8 is 1% D, 63% SVF, 1% HFIP, 8% B, 15% A, and 11% C. A small amount of HFEP was removed from the extract by washing with water. Distillation of the HC-0.8 extract gives 50-57% isolated yield of SVF.
Compound A can be reintroduced to the reaction mixture (see Example 8) and become the source of more SVF. Acetal C does not survive the distillation of the HC-0.8 extract, reverting to SVF and formaldehyde (see Example 7). Ethers D, E and polyethers of the generalized formula described above would also be expected to revert to their starting materials under reaction conditions. Thus, all the significant byproducts formed by the reaction of HFIP with HF and CH2O, as well as solvent and unreacted HFIP could be recycled making the new process environmentally and commercially more attractive than existing processes.
The invention will now be described in greater detail with reference to the following, non-limiting examples: